Metal Gear Solid 4 once again puts players in control of Solid Snake, the protagonist of the first two Metal Gear Solid games. Snake, who has noticeably aged since his last appearance (possibly due to being a clone) will once again take on Liquid Snake, this time in the body of Revolver Ocelot. Metal Gear Solid 4 takes place five years after Metal Gear Solid 2.

Hideo Kojima has said that this will be the last Metal Gear Solid game developed by him and that this will be the last game starring Solid Snake.